Solabegron zwitterion and uses thereof

ABSTRACT

This application relates to solabegron zwitterion useful for the treatment of lower urinary tract symptoms such as, for example, overactive bladder and prostate disorders. Additionally, this application relates to pharmaceutical compositions and methods of treatment utilizing the solabegron zwitterion for treating lower urinary tract symptoms. This application also relates to methods of preparing solabegron hydrochloride from the solabegron zwitterion.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a continuation application of U.S.application Ser. No. 16/018,945, filed Jun. 26, 2018 entitled“Solabegron Zwitterion and Uses Thereof”, which is a divisionalapplication of U.S. application Ser. No. 15/332,956, filed Oct. 24, 2016entitled “Solabegron Zwitterion and Uses Thereof”; which claims thebenefit of U.S. Provisional Application No. 62/245,656, filed Oct. 23,2015; U.S. Provisional Application No. 62/245,670, filed Oct. 23, 2015;U.S. Provisional Application No. 62/345,327, filed Jun. 3, 2016; U.S.Provisional Application No. 62/345,357, filed Jun. 3, 2016; and U.S.Provisional Application No. 62/345,574, filed Jun. 3, 2016 thedisclosures of which are hereby incorporated by reference in theirentirety.

SUMMARY

Embodiments of this application relate to processes for the preparationof the β-3-adrenoceptor agonist solabegron, and compounds useful in theprocesses for the preparation of solabegron and compositions comprisingcompounds useful for therapeutic purposes.

β-adrenoceptors belong to the family of adrenoceptors which mediate thephysiological actions of the hormones adrenaline and noradrenaline. Suchreceptors have been described for example by J R S Arch et. al., Nature,309, 163-165 (1984); C Wilson et. al., Eur. J. Pharmacol., 100, 309-319(1984); L J Emorine et. al., Science, 245, 1118-1121 (1989); and A.Bianchetti et. al. Br. J. Pharmacol., 100, 831-839 (1990).

Phenethanolamine derivatives having activity at 3-adrenoceptors aredisclosed in, for example, European Patent Applications EP-A-0455006 andEP-A-0543662.

Sub-types of the adrenoceptors, α₁-, α₂-, β₁-, β₂- and β₃- can beidentified on the basis of their pharmacological properties andphysiological effects. Chemical agents which stimulate or block thesereceptors (but not .β₃) are widely used in clinical medicine. Morerecently, emphasis has been placed upon specific receptor selectivity inorder to reduce side effects caused, in part, by interactions with otherreceptors.

β-adrenoceptors (β₃ and/or beta-3) are known to occur in adipose tissueand the gastrointestinal tract. Compounds having β-adrenoceptor agonistactivity have also been described as being useful in the treatment ofhyperglycemia; as being useful in the treatment of lower urinary tractsymptoms such as, for example, overactive bladder and prostatedisorders; as animal growth promoters; as blood platelet aggregationinhibitors; as positive inotropic agents; as antiatherosclerotic agents;and as being useful in the treatment of glaucoma.

A particularly useful beta-3 adrenoceptor agonist is3′-[(2-{[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino}ethyl)amino]biphenyl-3-carboxylicacid (hereinafter “solabegron”) Formula I:

Solabegron is described and claimed in U.S. Pat. No. 6,251,925 as acompound, pharmaceutical composition and method of treatment anddescribed and claimed in U.S. Pat. No. 8,642,661 and United StatesPatent Publication No. 2013/0172277A1 as a combination therapy with ananti-muscarinic agent. Additionally, Ohlstein, et. al. have demonstratedthat solabegron significantly reduced the symptoms of OAB in women withmoderate to severe OAB, showing that solabegron is safe, well tolerated,and does not demonstrate significant differences in adverse events ascompared to placebo. Ohlstein, E. H., et al., A Multicenter,Double-Blind, Randomized, Placebo-controlled Trial of the33-Adrenoceptor Agonist Solabegron for Overactive Bladder, Eur. Urol.,2012, 62(5), 834-40. U.S. Provisional Patent Application No. 62/020,889describes a drug interaction study conducted in healthy humanvolunteers, using repeat oral doses of solabegron and oxybutyninadministered singly as well as in combination with each other, in orderto assess the effects on pharmacokinetic and pharmacodynamic parameters,as measured by post void residual (PVR) volumes.

In view of the above disclosed beneficial therapeutic properties ofsolabegron it is therefore desirable to produce solabegron on a largerscale. Unfortunately, the laboratory scale method for preparingsolabegron disclosed in U.S. Pat. No. 6,251,925, while providingpharmaceutical quality material, is not amenable to production scale.Therefore a need exists for a large scale process for the production ofpharmaceutical grade solabegron. In addition, a need exists foralternative forms of solabegron that may be useful in compositions fortherapeutic purposes.

In one embodiment the present application describes a solid compoundaccording to Formula II:

or a pharmaceutically acceptable salt or a stereoisomer or a solvate ora polymorph thereof.

In one embodiment the present application describes a pharmaceuticalcomposition comprising: a therapeutically effective amount of a compoundaccording to Formula II:

or a pharmaceutically acceptable salt or a stereoisomer or a solvate ora polymorph thereof; and at least one pharmaceutically acceptablecarrier or excipient.

In one embodiment the present application describes a method fortreating lower urinary tract symptoms (hereinafter “LUTS”), comprisingadministering a therapeutically effective amount of a compound accordingto Formula II or a pharmaceutically acceptable salt or a stereoisomer ora solvate or a polymorph thereof to a patient in need thereof. Inanother embodiment the present application describes a method fortreating overactive bladder, comprising administering a therapeuticallyeffective amount of a compound according to Formula II or apharmaceutically acceptable salt or a stereoisomer or a solvate or apolymorph thereof to a patient in need thereof.

In one embodiment the present application describes a process forpreparing solabegron hydrochloride salt according to Formula I-HCl

comprising contacting a zwitterion of Formula II

with hydrochloric acid.

In one embodiment the present application describes a process forpreparing 3′-(2′methyl-4,5-dihydro-1H-imidazol-1-yl)-[1,1′]biphenyl-3-carboxylate according to Formula IV

or a pharmaceutically acceptable salt, stereoisomer, solvate orpolymorph thereof, comprising: contacting the biphenyl amineintermediate according to Formula V

with the acetimidoyl chloride according to Formula VI

wherein the acetimidoyl chloride according to Formula VI is generated insitu from the reaction of N-(2-chloroethyl)acetamide and phosphorylchloride.

In one embodiment the present invention describes a compound accordingto Formula III

or a pharmaceutically acceptable salt, stereoisomer, solvate, orpolymorph thereof.

In one embodiment the present invention describes a compound accordingto Formula IV

or a pharmaceutically acceptable salt, stereoisomer, solvate, orpolymorph thereof.

In one embodiment the present application describe a process forpreparing solabegron zwitterion according to Formula II

comprising contacting a solabegron sodium salt according to Formula I-Na

with hydrochloric acid.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1—is an FT-IR spectrum of the compound of Formula II, form I.

FIG. 2—is a Differential Scanning Calorimetry plot of the compound ofFormula II, form I.

FIG. 3—shows an X-Ray Powder Diffraction Pattern of the compound ofFormula II, form I.

FIG. 4—is a ¹H NMR spectrum of the compound of Formula II, form I.

FIG. 5—is a ¹³C NMR spectrum of the compound of Formula II, form I.

FIG. 6-1 to 6-3—shows the crystal morphology by Polarizing LightMicroscopy (PLM) of solabegron zwitterion, form I crystals; solabegronzwitterion, form II crystals obtained from Procedure A; and solabegronzwitterion, form II crystals obtained from Procedure B of Example 3.

FIG. 7—is an XRPD pattern of the solabegron zwitterion Form I (topline); solabegron zwitterion Form II, (middle) and solabegron HCl salt(bottom)

FIG. 8—is a TGA plot of solabegron zwitterion Form II (Top) vs.solabegron zwitterion Form I (bottom)

FIG. 9—The top plot is a DSC plot of solabegron zwitterion Form II thatreveals three thermal events, peaked around 67° C. (very broad), 131° C.(broad) and 180° C. (narrow), respectively; The bottom plot is a DCSplot of solabegron zwitterion Form I (around 184° C.) and solabegron HClsalt form I (around 223° C.).

FIG. 10—is a table which lists the testing conditions and results of therelative stability of solabegron zwitterion Forms I and II

FIG. 11—is XRPD data of Form I of the solebegron HCl salt (bottom)against a standard of solebegron HCl salt

FIG. 12—Shows PLM images of slurry samples from crystallization ofsolabegron HCl salt with feed solabegron zwitterion crystallized fromcrude solabegron sodium salt stock solution.

FIG. 13—is an XRPD peak list for the solabegron zwitterion, form I asmeasured on XRPD-1 Rigaku MiniFlex 600 (GMP instrument) under theexperimental parameters: X-Ray tube Cu (Kα); tube voltage 40 kV; tubecurrent 15 mA. Soller (Inc.) 2.5 deg.; IHS 10.0 mm; DS 1.250 deg.; SS1.250 deg.; Soller (rec.) 2.5 deg.; RS 0.15 monochromatization Kβ filter(X1); Scan from 2 to 40 degrees 2-theta; 0.01 degrees/step; scan rate 2degrees/min.

FIG. 14—is an XRPD peak list for the solabegron zwitterion, form II asmeasured on XRPD-1 Rigaku MiniFlex 600 (GMP instrument) under theexperimental parameters: X-Ray tube Cu (Kα); tube voltage 40 kV; tubecurrent 15 mA. Soller (Inc.) 2.5 deg.; IHS 10.0 mm; DS 1.250 deg.; SS1.250 deg.; Soller (rec.) 2.5 deg.; RS 0.15 monochromatization Kβ filter(X1); Scan from 2 to 40 degrees 2-theta; 0.01 degrees/step; scan rate 2degrees/min.

DETAILED DESCRIPTION

The present application describes processes for the preparation ofsolabegron zwitterion (Formula II) and solabegron HCl salt (Formula IHCl):

or a pharmaceutically acceptable salt, stereoisomer, solvate orpolymorph thereof.

Additionally, described herein are compounds useful for the preparationof the solabegron HCl, solabegron zwitterion or a pharmaceuticallyacceptable salt, stereoisomer, solvate or a polymorph thereof.

In addition, described herein is the use of solabegron zwitterion as atherapeutically beneficial treatment for overactive bladder and LUTS.

Pharmaceutical compositions containing solabegron zwitterion as well asmethods of treating overactive bladder and LUTS utilizing the solabegronzwitterion and the pharmaceutical compositions containing solabegronzwitterion are also described.

Definitions

This invention is not limited to the particular processes, compositions,or methodologies described, as these may vary. The terminology used inthe description is for the purpose of describing the particular versionsor embodiments only, and is not intended to limit the scope of thepresent invention. Unless defined otherwise, all technical andscientific terms used herein have the same meanings as commonlyunderstood by one of ordinary skill in the art. All publicationsmentioned herein are incorporated by reference in their entirety.Nothing herein is to be construed as an admission that the invention isnot entitled to antedate such disclosure by virtue of prior invention.

As used herein, the term “about” means plus or minus 10% of a givenvalue. For example, “about 50%” means in the range of 45%-55%.

As used herein the term “agonist” refers to a compound, the presence ofwhich results in a biological activity of a receptor that is the same asthe biological activity resulting from the presence of a naturallyoccurring ligand for the receptor.

The phrase “pharmaceutically acceptable” refers to molecular entitiesand compositions that are generally regarded as safe and nontoxic. Inparticular, pharmaceutically acceptable carriers, diluents or otherexcipients used in the pharmaceutical compositions of this applicationare physiologically tolerable, compatible with other ingredients, and donot typically produce an allergic or similar untoward reaction (e.g.,gastric upset, dizziness and the like) when administered to a patient.Preferably, as used herein, the term “pharmaceutically acceptable” meansapproved by a regulatory agency of the Federal or a state government orlisted in the U.S. Pharmacopoeia or other generally recognizedpharmacopoeia for use in animals, and more particularly in humans. Thephrase “pharmaceutically acceptable salt(s)”, as used herein, includesthose salts of compounds of the application that are safe and effectivefor use in mammals and that possess the desired biological activity.Pharmaceutically acceptable salts include salts of acidic or basicgroups present in compounds of the application or in compoundsidentified pursuant to the methods of the application. Pharmaceuticallyacceptable acid addition salts include, but are not limited to,hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate,phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate,citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate,maleate, genitsate, fumarate, gluconate, glucuronate, saccharate,formate, benzoate, glutamate, methanesulfonate, ethanesulfonate,benzensulfonate, p-toluenesulfonate and pamoate (i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Certain compounds ofthe application can form pharmaceutically acceptable salts with variousamino acids. Suitable base salts include, but are not limited to,aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, iron anddiethanolamine salts. Pharmaceutically acceptable base addition saltsare also formed with amines, such as organic amines. Examples ofsuitable amines are N,N′-dibenzylethylenediamine, chloroprocaine,choline, diethanolamine, dicyclohexylamine, ethylenediamine,N-methylglucamine, and procaine.

As used herein the phrase “lower urinary tract symptoms” or “LUTS”refers to a group of medical symptoms, comprising increased frequency ofurination, increased urinary urgency of urination, painful urination,excessive passage of urine at night, poor stream, overactive bladder,hesitancy, terminal dribbling, incomplete voiding and overflowincontinence.

As used herein the phrase “overactive bladder” or “OAB” refers to agroup of medical symptoms, comprising urinary urgency, frequenturination, nocturia, urinating unintentionally and urge incontinence.

As used herein, the term “therapeutic” means an agent utilized to treat,combat, ameliorate, protect against or improve an unwanted condition ordisease of a subject.

As used herein, the term “effective amount” refers to an amount thatresults in measurable inhibition of at least one symptom or parameter ofa specific disorder or pathological process.

As used herein the term “therapeutically effective amount” ofcompositions of the application is a predetermined amount which confersa therapeutic effect on the treated subject, at a reasonablebenefit/risk ratio applicable to any medical treatment. The therapeuticeffect may be objective (i.e., measurable by some test or marker) orsubjective (i.e., subject gives an indication of or feels an effect orphysician observes a change).

As used herein the terms “treat”, “treated”, or “treating” refer to boththerapeutic treatment and prophylactic or preventative measures, whereinthe object is to protect against (partially or wholly) or slow down(e.g., lessen or postpone the onset of) an undesired physiologicalcondition, disorder or disease, or to obtain beneficial or desiredclinical results such as partial or total restoration or inhibition indecline of a parameter, value, function or result that had or wouldbecome abnormal. For the purposes of this application, beneficial ordesired clinical results include, but are not limited to, alleviation ofsymptoms; diminishment of the extent or vigor or rate of development ofthe condition, disorder or disease; stabilization (i.e., not worsening)of the state of the condition, disorder or disease; delay in onset orslowing of the progression of the condition, disorder or disease;amelioration of the condition, disorder or disease state; and remission(whether partial or total), whether or not it translates to immediatelessening of actual clinical symptoms, or enhancement or improvement ofthe condition, disorder or disease. Treatment seeks to elicit aclinically significant response without excessive levels of sideeffects.

As used herein the terms, “pulse”, “pulses” “pulsed delivery” “pulsatiledelivery device” refer to pharmaceutical compositions and methods oftreatment wherein a therapeutic agent is delivered rapidly within ashort period of time, as a result of a biological or external trigger,after a specific lag time.

As used herein the term “immediate release” refers to pharmaceuticalcompositions that release the active ingredient within a small period oftime, typically less than 45 minutes.

As used herein the term “modified release” refers to pharmaceuticalcompositions that either release the active ingredient at a sustainedand controlled release rate over a period of time such as, for example,6 hours, 8 hours, 12 hours, 16 hours, and 24 hours or release thepharmaceutical dosage after a set time such as, for example,enteric-coated compositions that release the dosage in the intestinaltrack.

As used herein the terms “w/w”, v/v” wt %” and “weight %” refer toweight percent and/or volume percent of the named molecule in solution.

As used herein a solid of solabegron zwitterion is meant to include bothamorphous solids and crystalline solids.

Solabegron Zwitterion (Formula II)

In one embodiment the present application describes a compound accordingto Formula II:

or a pharmaceutically acceptable salt, stereoisomer, solvate orpolymorph. In some embodiments the compound of Formula II is a solid. Insome embodiments the compound of Formula II is an amorphous solid. Infurther embodiments the compound of Formula II is a crystal orcrystalline solid. In some embodiments the compound of Formula II is asingle polymorph. In further embodiments the compound of Formula II ismore than one polymorph. In some embodiments the compound of Formula IIis an anhydrous solid or crystal. In further embodiments, the compoundof Formula II is a solid or crystalline hydrate of isopropanol solvate.In some embodiments the compound of Formula II is characterized by apeak at 1552 cm¹ upon infrared analysis. In further embodiments thecompound of Formula II is characterized by a peak at about 184° C. upondifferential scanning calorimetry analysis. In further embodiments thecompound of Formula II is characterized by peaks at about 67° C. (verybroad), 131° C. (broad) and 180° C. upon differential scanningcalorimetry analysis. In some embodiments the compound of Formula II ischaracterized by an x-ray powder diffraction pattern having peaksexpressed in degrees 2θ (±2) at 6.3, 12.6; 18.6; 18.9; 20.9; 22.4; 25.3;and 25.5. In some embodiments the compound of Formula II ischaracterized by an x-ray powder diffraction pattern having peaksexpressed in degrees 2θ (±2) at 6.2, 12.5; 18.8; 20.6; and 25.2. In someembodiments the compound of Formula II is characterized by an x-raypowder diffraction pattern having peaks expressed in degrees 2θ (±2) at6.2, 12.5; 18.6; 18.8; 20.6; 22.3, and 25.2. In some embodiments thecompound of Formula II is characterized by an x-ray powder diffractionpattern having peaks expressed in degrees 2θ (±2) at 6.2, 12.5; 16.9,18.6; 18.8; 20.6; 21.1, 21.5; 22.3, 25.2; 26.6, and 32.9. In someembodiments the compound of Formula II is characterized by an x-raypowder diffraction pattern having peaks expressed in degrees 2θ (±2) at17.6, 18.7, 19.6, 20.1, 20.5, 23.7, and 25.8. In some embodiments thecompound of Formula II is characterized by an x-ray powder diffractionpattern having peaks expressed in degrees 2θ (±2) at 9.4, 15.1, 16.2,17.6, 18.7, 19.6, 20.1, 20.5, 21.8, 22.6, 23.7, 24.8, 25.8, and 28.9. Insome embodiments the compound of Formula II is characterized by an x-raypowder diffraction pattern having peaks expressed in degrees 2θ (±2) at6.1, 7.5, 9.4, 11.3, 14.5, 15.1, 16.2, 17.6, 18.7, 19.6, 20.1, 20.5,21.8, 22.6, 23.7, 24.8, 25.8, and 28.9. In further embodiments thecompound of Formula II, is characterized by ¹H NMR peaks (¹H NMR, 300MHz, DMSO-d₆) δ 8.15; 7.90; 7.70; 7.40; 7.30; 7.19; 6.82; 6.63; 6.00;4.83; 3.30; 2.95; and 2.82. In some embodiments the compound of FormulaII is characterized by ¹³C NMR of the peak (¹³NMR, 300 MHz, DMSO-d₆) δ170.0; 148.0; 145.5; 140.3; 140.1; 135.4; 133.9; 130.0; 129.6; 129.0;128.3; 128.0; 127.3; 127.1; 125.7; 124.5; 114.8; 111.8; 110.7; 62.8;54.8; 44.6; 40.8; 40.0; 39.8; 39.4; 39.2; 38.8; 38.6; and 25.4. Infurther embodiments the compound of Formula II is at least about 97.0%by weight pure. In some embodiments the compound of Formula II is atleast about 98.0% by weight pure. In some embodiments the compound ofFormula II is at least about 99.0% by weight pure. In furtherembodiments the compound of Formula II is at least about 99.5% by weighpure. In some embodiments the compound of Formula II is at least about99.9% by weight pure. In further embodiments the compound of Formula IIhas no single impurity present in an amount greater than about 0.5% byweight. In some embodiments the compound, of Formula II has no singleimpurity present in an amount greater than about 0.25% by weight. Infurther embodiments the compound of Formula II, has no single impuritypresent in an amount greater than about 0.10% by weight.

After extensive effort, applicants have newly discovered two crystallineforms of solabegron zwitterion. One form, form I, is an anhydrouscrystalline form and is characterized by an x-ray powder diffractionpattern having peaks expressed in degrees 2θ (±2) at 6.2, 12.5; 18.8;20.6; and 25.2. A second form, form II is a hydrate of isopropanolsolvate and is characterized by an x-ray powder diffraction patternhaving peaks expressed in degrees 2θ (±2) at 17.6, 18.7, 19.6, 20.1,20.5, 23.7, and 25.8. (See EXAMPLE 3 and FIGS. 7, 12 and 13). Applicantsalso discovered that the form II solabegron zwitterion is more stablethan the form I solabegron zwitterion and that the form II zwitterioncrystal form (see EXAMPLE 3 and FIG. 10) afforded powerful impurityrejection and robust isolation process which is a key component for ascalable solabegron HCl process. Solabegron zwitterion as describedherein is the least soluble form of solabegron, and that feature allowsit to be isolated in pure form, allowing for large scale production.After isolation the solabegron crystals can be dissolved and thencrystallized to the solabegron HCL salt form, which is currently beinginvestigated clinically. Of equal importance, the pharmaceuticalcompositions of solabegron zwitterion disclosed herein could be used asthe active ingredient clinically, replacing the need for the HCl saltform of solabegron.

Pharmaceutical Compositions of Solabegron Zwitterion (Formula II)

In one embodiment the present application describes a pharmaceuticalcomposition comprising: a therapeutically effective amount of a compoundaccording to Formula II:

or a pharmaceutically acceptable salt, stereoisomer, solvate orpolymorph; and at least one pharmaceutically acceptable carrier orexcipient. In some embodiments the compound of Formula II in thecomposition is a solid. In some embodiments the compound of Formula IIis amorphous. In further embodiments, the compound of Formula II in thecomposition is a crystal. In some embodiments, the compound of FormulaII in the composition is a single polymorph. In further embodiments thecompound of Formula II in the composition is more than one polymorph. Infurther embodiments, the compound of Formula II in the composition is asolid or crystalline hydrate of isopropanol solvate. In some embodimentsthe compound of Formula II in the composition is characterized by a peakat 1552 cm¹ upon infrared analysis. In further embodiments the compoundof Formula II in the composition is characterized by a peak at 184.6° C.upon differential scanning calorimetry analysis. In some embodiments thecompound of Formula II in the composition is characterized by an x-raypowder diffraction pattern having peaks expressed in degrees 2θ (±2) at6.3, 12.6; 18.6; 18.9; 20.9; 22.4; 25.3; and 25.5. In some embodimentsthe compound of Formula II in the composition is characterized by anx-ray powder diffraction pattern having peaks expressed in degrees 2θ(±2) at 6.2, 12.5; 18.8; 20.6; and 25.2. In some embodiments thecompound of Formula II in the composition is characterized by an x-raypowder diffraction pattern having peaks expressed in degrees 2θ (±2) at6.2, 12.5; 18.6; 18.8; 20.6; 22.3, and 25.2. In some embodiments thecompound of Formula II in the composition is characterized by an x-raypowder diffraction pattern having peaks expressed in degrees 2θ (±2) at6.2, 12.5; 16.9, 18.6; 18.8; 20.6; 21.1, 21.5; 22.3, 25.2; 26.6, and32.9. In some embodiments the compound of Formula II in the compositionis characterized by an x-ray powder diffraction pattern having peaksexpressed in degrees 2θ (±2) at 17.6, 18.7, 19.6, 20.1, 20.5, 23.7, and25.8. In some embodiments the compound of Formula II in the compositionis characterized by an x-ray powder diffraction pattern having peaksexpressed in degrees 2θ (±2) at 9.4, 15.1, 16.2, 17.6, 18.7, 19.6, 20.1,20.5, 21.8, 22.6, 23.7, 24.8, 25.8, and 28.9. In some embodiments thecompound of Formula II in the composition is characterized by an x-raypowder diffraction pattern having peaks expressed in degrees 2θ (±2) at6.1, 7.5, 9.4, 11.3, 14.5, 15.1, 16.2, 17.6, 18.7, 19.6, 20.1, 20.5,21.8, 22.6, 23.7, 24.8, 25.8, and 28.9. In further embodiments thecompound of Formula II, in the composition is characterized by ¹H NMRpeaks (¹H NMR, 300 MHz, DMSO-d₆) δ 8.15; 7.90; 7.70; 7.40; 7.30; 7.19;6.82; 6.63; 6.00; 4.83; 3.30; 2.95; and 2.82. In some embodiments thecompound of Formula II in the composition is characterized by ¹³C NMR ofthe peak (¹³NMR, 300 MHz, DMSO-d₆) δ 170.0; 148.0; 145.5; 140.3; 140.1;135.4; 133.9; 130.0; 129.6; 129.0; 128.3; 128.0; 127.3; 127.1; 125.7;124.5; 114.8; 111.8; 110.7; 62.8; 54.8; 44.6; 40.8; 40.0; 39.8; 39.4;39.2; 38.8; 38.6; and 25.4. In further embodiments the compound ofFormula II in the composition is at least about 97.0% by weight pure. Insome embodiments the compound of Formula II in the composition is atleast about 98.0% by weight pure. In some embodiments the compound ofFormula II in the composition is at least about 99.0% by weight pure. Infurther embodiments the compound of Formula II in the composition is atleast about 99.5% by weigh pure. In some embodiments the compound ofFormula II in the composition is at least about 99.9% by weight pure. Infurther embodiments the compound of Formula II in the composition has nosingle impurity present in an amount greater than about 0.5% by weight.In some embodiments the compound, of Formula II in the composition hasno single impurity present in an amount greater than about 0.25% byweight. In further embodiments the compound of Formula II, in thecomposition has no single impurity present in an amount greater thanabout 0.10% by weight.

In some embodiments, the composition further comprises one or moreadditional therapeutic agents for the treatment of LUTS and/or OAB,wherein the one or more additional therapeutic agents is selected fromthe group consisting of: antimuscarinic agents; alpha adrenoceptorblockers; 5-alpha reductases; and phosphdiesterases-5 inhibitors.

The pharmaceutical compositions of the present application can beadministered for any of the uses described herein by any suitable means,for example, orally, such as in the form of tablets, capsules, granulesor powders; sublingually; bucally; vaginally, such as via intravaginalring; parenterally, such as by subcutaneous, intravenous, intramuscular,or intrasternal injection or infusion techniques (e.g., as sterileinjectable aqueous or non-aqueous solutions or suspensions); in dosageunit formulations containing non-toxic, pharmaceutically acceptablevehicles or diluents. The present compositions can, for example, beadministered in a form suitable for immediate release or extendedrelease. Immediate release or extended release can be achieved by theuse of suitable pharmaceutical compositions comprising the presentcompounds, or, particularly in the case of extended release, by the useof devices such as subcutaneous implants or osmotic pumps. The presentcompositions can also be administered liposomally.

The pharmaceutical composition of the present invention can formulatedfor a pulsatile drug-delivery system wherein the composition releases atleast two pulses of the compound according to Formula II, wherein afirst pulse achieves a first target C_(max), a second pulse achieves asecond target C_(max), a first target C_(min) is achieved between thefirst pulse and the second pulse and a second C_(min) is achieved afterthe second pulse.

The formulation for a beta 3 adrenoceptor agonist can significantlymodify the absorption profile. For example, some compounds aredifferentially absorbed in different regions of the GI tract. Some ofthe factors involved in absorption can include pH-dependent solubility,particle size, lipophilicity, ionization, GI-motility or transporters.Accordingly, the solabegron zwitterion and pharmaceutical salts thereofdisplay the optimum absorption in the proximal GI tract. Pharmaceuticalcompositions are presented herein that improve the pH-dependentsolubility of the solabegron zwitterion in the distal GI tract. Underthese improved conditions, a second pulse of the solabegron zwitterionrelease and absorption will result. Additionally, methods for therelease of the solabegron zwitterion in the distal GI tract based on pHare presented herein.

Another example of producing a delayed second pulse is based on thetransit time of the dosage form. This is achievable through thetime-dependent erosion of the dosage form coating. The GI transit timeis well understood, and the coatings are designed to erode within aspecific time range that corresponds to a specific region within the GItract. Pharmaceutical compositions and methods of use are presentedherein for the release of the dosage form on time-dependent erosion.

Exemplary compositions for oral administration include emulsions andsuspensions which can contain, for example, microcrystalline cellulosefor imparting bulk, alginic acid or sodium alginate as a suspendingagent, methylcellulose as a viscosity enhancer, and sweeteners orflavoring agents such as those known in the art; and immediate releasetablets which can contain, for example, microcrystalline cellulose,dicalcium phosphate, starch, magnesium stearate and/or lactose and/orother excipients, binders, extenders, disintegrants, diluents andlubricants such as those known in the art. The compositions of thepresent application can also be delivered through the oral cavity bysublingual and/or buccal administration. Molded tablets, compressedtablets or freeze-dried tablets are exemplary forms which may be used.Exemplary compositions include those formulating the present beta-3adrenoceptor agonists with fast dissolving diluents such as mannitol,lactose, sucrose and/or cyclodextrins. The compositions of the presentapplication may take the form of pulsatile delivery systems such as, forexample, PULSINCAP®, MICROPUMP®, MEDUSA™, PORT® system, CHRONOTROPIC®,TIME CLOCK®, multilayered tablets, DiffuCORE®, rupturable tablets,ACCU-BREAK® system, DIFFUCAPS®, DIFFUTABS®, Eurand MINITABS®,MICROCAPS®, SODAS®, IPDAS®, OsDrC®, OptiDose™, OptiMelt™, ZYDIS®,CODAS®, PRODAS®, TMDS®, DMDS®, PMDS®, GEOCLOCK®, GEOMATRIX®, PULSYS®,OROS® INTELLIMATRIX™ and VERSETROL™. Also included in such formulationsmay be high molecular weight excipients such as celluloses (avicel) orpolyethylene glycols (PEG). Such formulations can also include anexcipient to aid mucosal adhesion such as hydroxy propyl cellulose(HPC), hydroxy propyl methyl cellulose (HPMC), sodium carboxy methylcellulose (SCMC), maleic anhydride copolymer (e.g., Gantrez), and agentsto control release such as polyacrylic copolymer (e.g. Carbopol 934).Lubricants, glidants, flavors, coloring agents and stabilizers may alsobe added for ease of fabrication and use.

The therapeutic agents in the pharmaceutical compositions of the presentapplication may exist in any physical form known to one of skill in theart such as, for example, nanoparticles, crystalline solids, amorphoussolids, polymorphs, pharmaceutically acceptable salts, hydrates,solvates, stereoisomers, solutions and suspensions. Crystalline solidshave regular ordered arrays of components held together by uniformintermolecular forces, whereas the components of amorphous solids arenot arranged in regular arrays. Hydrates are substances that incorporatewater molecules into their crystalline matrix. Solvates are substancesthat incorporate solvent molecules into their crystalline matrix.Polymorphs exhibit different crystalline structures for molecules thathave the same molecular formula and sequence of bonded atoms.Stereoisomers are isomeric molecules that have the same molecularformula and sequence of bonded atoms (constitution), but that differonly in the three-dimensional orientations of their atoms in space.

Exemplary compositions for parenteral administration include injectablesolutions or suspensions which can contain, for example, suitablenon-toxic, parenterally acceptable diluents or solvents, such asmannitol, 1,3-butanediol, water, Ringer's solution, an isotonic sodiumchloride solution, or other suitable dispersing or wetting andsuspending agents, including synthetic mono- or diglycerides, and fattyacids, including oleic acid, or Cremaphor.

Exemplary compositions for transdermal administration includetransdermal therapeutic systems (hereinafter “TTS”). TTS are patcheshaving a layered structure and comprising at least one activepharmaceutical ingredient in a reservoir layer. A distinction is madebetween matrix-type and reservoir-type TTS: in the first case thereservoir layer containing the active pharmaceutical ingredient has apressure-sensitive adhesive finish, and in the second case a membranewhich controls the rate of release of the active pharmaceuticalingredient, and where appropriate an additional pressure-sensitiveadhesive layer, are present.

It will be understood that the specific dose level and frequency ofdosage for any particular subject can be varied and will depend upon avariety of factors including the activity of the specific beta-3adrenoceptor agonist employed, the metabolic stability and length ofaction of that compound, the species, age, body weight, general health,sex and diet of the subject, the mode and time of administration, rateof excretion, drug combination, and severity of the particularcondition.

Method of Treating LUTS and/or OAB

In one embodiment the present application describes a method fortreating LUTS, comprising: administering a therapeutically effectiveamount of a compound according to Formula II or a pharmaceuticallyacceptable salt, stereoisomer, solvate or polymorph to a patient in needthereof. Further embodiments of the application describe the method,wherein the LUTS is overactive bladder. Further embodiments of theapplication describe the method, wherein the LUTS is prostate disorder.Further embodiments of the application describe the method, wherein theLUTS exhibits symptoms selected from the group consisting of: frequencyof urinary urgency; nocturia; increase in urinary micturition frequency;and urinary incontinence.

In one embodiment the present application describes a method fortreating LUTS, comprising: administering a therapeutically effectiveamount of a pharmaceutical composition comprising a therapeuticallyeffective amount of a compound according to Formula II or apharmaceutically acceptable salt, stereoisomer, solvate or polymorph anda pharmaceutically acceptable carrier or diluent to a patient in needthereof. Further embodiments of the application describe the method,wherein the LUTS is overactive bladder. Further embodiments of theapplication describe the method, wherein the LUTS is prostate disorder.Further embodiments of the application describe the method, wherein theLUTS exhibits symptoms selected from the group consisting of: frequencyof urinary urgency; nocturia; increase in urinary micturition frequency;urinary incontinence and reduction in voided volume.

Therapeutically effective amounts of the compound according to FormulaII:

or a pharmaceutically acceptable salt or a stereoisomer or a solvate ora polymorph thereof may be from about 50 mg to about 1 gm, from about100 mg to about 600 mg, from about 100 mg to about 500 mg, from about100 mg to about 300 mg, from about 100 mg to 200 mg, from about 150 mgto about 300 mg, from about 150 mg to about 200 mg, from about 175 mg toabout 300 mg, about 50 mg, about 100 mg, about 150 mg, about 175 mg,about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg,about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg,about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg,about 850 mg, about 900 mg, about 950 and about 1 gm. Thistherapeutically effective amount may be administered once a day, twice aday or three times a day.

In some embodiments the total daily dose is from 175 mg to 300 mg. Insome embodiments the total daily dose is 175 mg, 200 mg, 225 mg, 250 mg,275 mg, Or 300 mg.

In some embodiments, the method further comprises administering one ormore additional therapeutic agents for the treatment of LUTS and/or OAB,wherein the one or more additional therapeutic agents is selected fromthe group consisting of: antimuscarinic agents; alpha adrenoceptorblockers; 5-alpha reductases; and phosphdiesterases-5 inhibitors.

Pharmaceutical Combinations

The present application also includes within its scope pharmaceuticalcompositions comprising, as an active ingredient, a therapeuticallyeffective amount of the solabegron zwitterion, alone or in combinationwith a pharmaceutical carrier or diluent. Optionally, the pharmaceuticalcompositions of the present invention can be used alone, or incombination with other suitable therapeutic agents useful in thetreatment of the LUTS including: antimuscarinic agents, alphaadrenoceptor blockers, 5-alpha reductases and phosphodiesterase-5inhibitors.

Such other therapeutic agent(s) may be administered prior to,simultaneously with, or following the administration of the beta-3adrenoceptor agonist containing pharmaceutical composition in accordancewith the invention.

Examples of suitable antimuscarinic agents for use in combination withthe pharmaceutical compositions of the present application includetolterodine, oxybutynin, trospium, solifenacin, darifenacin,propiverine, fesoterodine, and pharmaceutically acceptable saltsthereof.

Examples of suitable alpha adrenoceptor blockers for use in combinationwith the pharmaceutical compositions of the present application includetamuslosin, alfuzosin, and silodosin.

Examples of suitable 5-alpha reductases for use in combination with thepharmaceutical compositions of the present application includefinasteride, dutaseteride and pharmaceutically acceptable salts thereof.

Examples of suitable phosphodiesterase-5 inhibitors for use incombination with the pharmaceutical compositions of the presentapplication include sildenafil, tadalafil, vardenafil, udenafil,avanafil and pharmaceutically acceptable salts thereof.

Synthesis

Solabegron (Formula I), solabegron hydrochloride salt, (Formula I-HCl),the solabegron zwitterion (Formula II) or a another pharmaceuticallyacceptable salt or a stereoisomer or a solvate or a polymorph thereofmay be prepared by the following synthetic routes as illustrated below.

A mixture of (3-nitrophenyl)boronic acid and methyl 3-bromobenzoate wasplaced into a reaction vessel with 10% palladium on carbon (Pd/C) andsodium carbonate (Na2CO₃) in methanol (MeOH). The reaction mixture washeld at reflux until the starting materials had been converted intomethyl 3′-nitro-[1,1′-biphenyl]-3-carboxylate. The methyl3′-nitro-[1,1′-biphenyl]-3-carboxylate was maintained in the reactionvessel, used without purification, isopropyl acetate was added to thereaction vessel and the mixture subsequently reacted with 10% Pd/C in ahydrogen atmosphere to yield methyl3′-amino-[1,1′-biphenyl]-3-carboxylate according to Formula V.N-(2-chloroethyl)acetamide was reacted with 2.5 equivalents ofphosphoryl chloride (POCl₃) in ethyl acetate (EtOAc) on warming from 0to 25° C. to yield (Z)—N-(2-chloroethyl)acetimidoyl chloridedichlorophosphate according to Formula VI that was added withoutpurification to methyl 3′-nitro-[1,1′-biphenyl]-3-carboxylate accordingto Formula V to yield methyl(E)-3′-N-(2-chloroethyl)acetimiamido-[1,1′-biphenyl]-3-carboxylatehydrochloride according to Formula VII that was used withoutpurification. To the reaction vessel was added 5.33 equivalents of NH₃as a saturated aqueous solution (approximately 35% NH₃ by mass). Theresulting reaction mixture yielded methyl3′-(2′methyl-4,5-dihydro-1H-imidazol-1-yl)-[1,1′]biphenyl-3-carboxylateaccording to Formula IV.

The coupling of the imidazoline ring on the compound according toFormula IV with the epoxide ring of (R)-2-(3-chlorophenyl)oxirane yieldsmethyl3′-((2R)-2-(3-chlorophenyl)-7a-methyltetrahydroimidazol[2,1,b]oxazole-7(7aH)-yl)-[1,1′-biphenyl]-3-carboxylateaccording to Formula III that opens upon treatment with from about 1 toabout 5 equivalents sodium hydroxide (about 5% to about 50% w/w) toyield the solabegron sodium salt according to Formula I-Na.

The recovered solabegron sodium salt according to Formula I-Na wasutilized without purification. The addition of about 25% w/w NaOHsolution yielded a slurry that was slowly neutralized at 55° C. withabout 0.9 equivalents of 1N HCl. After approximately 50% of the HCl hadbeen added 2% by weight of the solabegron zwitterion according toFormula II was added to the reaction mixture to induce crystallizationof the solabegron zwitterion according to Formula II. The solabegronzwitterion was collected, dried and checked for purity before beingconverted into the solabegron hydrochloride salt according to FormulaI-HCl by the slow addition of 1.0 equivalent of 1N HCl to a slurry ofthe solabegron zwitterion in water as illustrated in Scheme 3.

Process for Preparing Solabegron

In one embodiment the present application describes processes for makingsolabegron according to Formula I

comprising contacting the imidazo[2,1,b]oxazole intermediate accordingto Formula III

with aqueous sodium hydroxide (NaOH) in a reaction vessel.

In one embodiment the present application describes processes for makingsolabegron hydrochloride salt according to Formula I-HCl

comprising: contacting the imidazo[2,1,b]oxazole intermediate accordingto Formula III

with aqueous sodium hydroxide (NaOH) in a reaction vessel. Furtherembodiments describe processes, wherein the NaOH is present from about 1equivalent to about 5 equivalents. Further embodiments describeprocesses, wherein the reaction vessel additionally contains isopropylalcohol. Further embodiments describe processes, wherein solabegronhydrochloride salt is formed by the addition of hydrochloric acid (HCl)to the reaction vessel.

In one embodiment the present application describes processes for makingthe hydrochloride salt of solabegron according to Formula I-HCl

comprising contacting a zwitterion of Formula II

with hydrochloric acid in a reaction vessel. Further embodimentsdescribe processes wherein the HCl is 6N HCl. Further embodimentsdescribe processes wherein the HCl to zwitterion ratio is 1.2equivalents. Further embodiments describe processes that include seedingthe reaction mixture to induce crystallization. Further embodimentsdescribe processes wherein the reaction temperature is 50-62° C. Furtherembodiments describe processes wherein the solvent is IPA H₂O. Furtherembodiments describe processes wherein the seed load is 05-5%. Furtherembodiments describe processes wherein the seeding point pH is 6.6-7.2.

In one embodiment the present application describes processes formaking, zwitterion of Formula II,

comprising contacting a sodium salt according to Formula I-Na

with hydrochloric acid.

In one embodiment the present application describes processes for makingthe sodium salt according to Formula I-Na

comprising contacting an imidazo[2,1,b]oxazole intermediate according toFormula III

with aqueous sodium hydroxide (NaOH) in a reaction vessel. Furtherembodiments describe processes, wherein the NaOH is present from about 1equivalent to about 5 equivalents. Further embodiments describeprocesses, wherein the reaction vessel additionally contains isopropylalcohol.

In one embodiment the present application describes processes for makingimidazo[2,1,b]oxazole intermediate according to Formula III

comprising contacting methyl3′-(2′methyl-4,5-dihydro-1H-imidazol-1-yl)-[1,1′]biphenyl-3-carboxylateaccording to Formula IV

with (R)-2-(3-chlorophenyl)oxirane.

In one embodiment the present application describes processes for makingmethyl3′-(2′methyl-4,5-dihydro-1H-imidazol-1-yl)-[1,1′]biphenyl-3-carboxylateaccording to Formula IV or a pharmaceutically acceptable salt or astereoisomer or a solvate or a polymorph thereof

comprising contacting the biphenyl amine according to Formula V

with the acetimidoyl chloride according to Formula VI

wherein the acetimidoyl chloride is generated in situ from the reactionof N-(2-chloroethyl)acetamide and phosphoryl chloride. Furtherembodiments describe processes, wherein the phosphoryl chloride ispresent from about 1 equivalent to about 5 equivalents. Furtherembodiments describe processes, wherein the phosphoryl chloride isdissolved in ethyl acetate (EtOAc). Further embodiments describeprocesses, wherein the biphenyl aniline according to Formula V and theacetimidoyl chloride according to Formula VI react to form theacetimiamido biphenyl according to Formula VII

or a pharmaceutically acceptable salt or a stereoisomer or a solvate ora polymorph thereof.

In one embodiment the present application describes processes for makingthe biphenyl amine according to Formula V

comprising coupling (3-nitrophenyl)boronic acid and methyl3-bromobenzoate

In one embodiment the present application describes processes for makingthe solabegron sodium salt according to Formula I-Na

comprising: contacting the imidazo[2,1,b]oxazole intermediate accordingto Formula III

with aqueous sodium hydroxide (NaOH)

In one embodiment the present application describes a compound accordingto Formula III or a pharmaceutically acceptable salt or a stereoisomeror a solvate or a polymorph thereof.

In one embodiment the present application describes a compound accordingto Formula IV or a pharmaceutically acceptable salt or a stereoisomer ora solvate or a polymorph thereof.

EXAMPLES Example 1: Preparation of methyl3′-(2′methl-4,5-dihydro-1H-imidazol-1-yl)-[1,1′]biphenyl-3-carboxylate(Formula IV)

A mixture of (3-nitrophenyl)boronic acid and methyl 3-bromobenzoate wasplaced into a reaction vessel with 10% palladium on carbon (Pd/C) andsodium carbonate (Na₂CO₃) in methanol (MeOH). The reaction mixture washeld at reflux until the starting materials had been converted intomethyl 3′-nitro-[1,1′-biphenyl]-3-carboxylate. The methyl3′-nitro-[1,1′-biphenyl]-3-carboxylate was maintained in the reactionvessel, used without purification, isopropyl acetate was added to thereaction vessel and the mixture subsequently reacted with 10% Pd/C in ahydrogen atmosphere to yield methyl3′-amino-[1,1′-biphenyl]-3-carboxylate.

Concurrently, N-(2-chloroethyl)acetamide was reacted 2.5 equivalents ofphosphoryl chloride (POCl₃) in ethyl acetate (EtOAc) on warming from 0to 25° C. to yield (Z)—N-(2-chloroethyl)acetimidoyl chloridedichlorophosphate.

The (Z)—N-(2-chloroethyl)acetimidoyl chloride dichlorophosphate wasadded without purification to methyl3′-nitro-[1,1′-biphenyl]-3-carboxylate to yield methyl(E)-3′-N-(2-chloroethyl)acetimiamido-[1,1′-biphenyl]-3-carboxylatehydrochloride that was used without purification. To the reaction vesselwas added 5.33 equivalents of NH₃ as a saturated aqueous solution(approximately 35% NH₃ by mass). The resulting reaction mixture yieldedthe desired methyl 3′-(2′methl-4,5-dihydro-1H-imidazol-1-yl)-[1,1′]biphenyl-3-carboxylate (Formula IV).

Example 2: Preparation of Solabegron Sodium Salt (Compound of FormulaI-Na)

Step 1: Preparation of Intermediate Formula III via alkylation of methyl3′-(2′methyl-4,5-dihydro-1H-imidazol-1-yl)-[1,1′]biphenyl-3-carboxylate(Formula IV)

Methyl3′-(2′methl-4,5-dihydro-1H-imidazol-1-yl)-[1,1′]biphenyl-3-carboxylate(Formula IV, 205.2 g, 96.6 wt %, 67.4 mmol, 1.0 eq) and toluene (1 L, 5Vol) were added to a 2-L round bottom flask, and the resulting slurrywas heated to 55-60° C. in a heating bath to dissolve. The resultingsolution was concentrated on a rotary evaporator under partial vacuum(80-115 mbar) at bath temperature of 50-55° C. to ˜⅓ of the originalvolume. Toluene (1 L, 5 Vol) was added to the reaction mixture and theresulting solution was concentrated a second time on a rotary evaporatorunder partial vacuum (80-115 mbar) at bath temperature of 50-55° C. to˜⅓ of the original volume. Toluene (1 L, 5 Vol) was added to thereaction mixture and the resulting solution was concentrated a thirdtime on a rotary evaporator under partial vacuum (80-115 mbar) at bathtemperature of 50-55° C. to ˜⅓ of the original volume. The KF waschecked and found to be within an acceptable range (KF=49 ppm, 24.3μg/0.5 mL) so the reaction mixture was allowed to continue toconcentrate on the rotary evaporator to ˜300 mL. The concentrates weretransferred to a 1-L jacketed vessel and rinsed with toluene and thebatch volume was 400 mL. The toluene mixture was then heated to 60° C.,add (R)-3-chlorostyrene oxide (100.0 g, 647 mmol, 0.96 eq) was added inone portion. The reaction mixture was heated to 120° C. over 15-30 minand maintained at 120° C. for 20-22 h. The reaction mixture (orangesolution) was sampled by taking about 5 μL liquid into a LC vial,diluting with MeCN to ˜1.2 mL for HPLC analysis. The conversion wasfound to be 94.3 A % (spec≥96 A %, the ratio of LC area percent ofCompound of Formula III to the combined area % of methyl3′-(2′methl-4,5-dihydro-1H-imidazol-1-yl)-[1,1′ ]biphenyl-3-carboxylate(Compound of Formula IV) and Compound of Formula III). Therefore thereaction was stopped by cooling to 45-50° C.

Step 2: Conversion of Intermediate Formula III to Solabegron-Na(Compound of Formula I-Na)

After completion of the alkylation reaction, the crude IntermediateFormula III reaction mixture of Step 1, was transferred to a 3 L roundbottom flask with a heating mantle and magnetic stirrer. The solutionwas heated to 60-70° C., and IPA (900 mL) was added while maintainingthe same temperature. 25% w/w NaOH aqueous solution (323.5 g, ˜249 mL)and water (840 mL) were added to the reaction mixture slowly, whilemaintain the temperature at 60-70° C. The toluene was remove from thereaction mixture by atmospheric distillation. The initial temperature is78° C. when the distillation starts. When a total of ˜1 L distillate iscollected (temperature is 81-83° C.), the distillation is ended byadding IPA (620 mL). The mixture was then heated to 81-83° C. undergentle reflux and kept at the same temperature for 15 h. A 5 L sample ofthe reaction mixture was removed, the sample was diluted with 30:70 v/vMeCN/H₂O to ˜1.2 mL and analyzed by HPLC analysis which indicated thatthe Intermediate Formula II was fully converted to the solabegron sodiumsalt (Compound of Formula I-Na). The reaction mixture was cooled to 40°C. Activated Carbon, Decolorizing (58 g) was added to the batch solutionin one portion at 40° C. The resulting black mixture was stirred at 40°C. for 2 h. The mixture was then filtered (Solka Floc® (80 g) was addedto a 2 L sintered glass funnel and pre-washed with 1:1 v/v IPA/water2×300 mL. Used solvents were discarded by filtration) to remove usedsolid charcoal and the black cake was washed with 1:1 v/v IPA/water1×200 mL. The combined filtrate was passed through a 0.45 micron PTFEin-line filter as a polish filtration, giving solabegron-Na stocksolution (2195 g, 10.5 wt %) in 83% overall yield from methyl3′-(2′methl-4,5-dihydro-1H-imidazol-1-yl)-[1,1′]biphenyl-3-carboxylate(Formula IV).

Example 3: Preparation of the Solabegron Zwitterion (Formula II) fromSolabegron-Na (Compound of Formula I-Na)

Solabegron Zwitterion Form I

37.1 mL of solabegron sodium salt (equivalent to 5.91 g of HCl salt,13.2 mmol) was added to an EasyMax 100 mL vessel, IPA/water=˜20:80 v/v.Agitation was set at 400 rpm and the reaction mixture was heated to 55°C. 1N HCl was added via syringe pump at rate of 3.3 mL/h at 55° C. After12.5 mL 1N HCl was added, the batch turned hazy. Solabegron zwitterionseed (596-106, 59 mg) was added in one portion. Solabegron zwitterionseed did not survive. After a total of 15 mL 1N HCl was added, a 2ndportion of solabegron seed (596-106, 59 mg) was added. Solabegron seeddid not survive again. After a total of 17 mL 1N HCl was added, a 3rdportion of solabegron zwitterion seed (596-106, 59 mg) was added.Solabegron zwitterion seed did survive this time. A total of 25 mL 1NHCl (1.89 eq) was added to reach a pH 7.8 (vs. 9.5 with purifiedsolabegron). The mixture was aged at 55° C. for 1 h, cooled to 25° C.over 3 h, then at RT for the overnight. Slurry was isolated byfiltration, the wet cake was washed with 1:9 v/v IPA/water 1×30 mL,followed by water 2×30 mL. After drying at ambient temperature undervacuum for 5 h, the partially dried solabegron zwitterion as beige solid(4.55 g after subtracting seed) was analyzed by LC assay giving 95.6 A %(87.6 wt %) in 83.8% isolated yield (corrected with wt %). FIG. 6

Solabegron Zwitterion Form II

Procedure A: HCl in Water Procedure

Solabegron-Na stock solution (50.0 g, 10 wt % in 1:1 v/v IPA/water,equiv to 5.0 g of solabegron zwitterion, 12.17 mmol) was charged intoEasyMax 100 mL vessel with temperature probe, pH probe (pre-calibratedat pH 4.00, 7.00, and 10.00), condenser and nitrogen bubbler. Theignition agitation rate was set to 450 rpm. The reaction mixture washeated to 55° C. over 30 min. The reaction mixture had a pH of 13.3. 1NHCl was added in water at the rate of 7.5 mL/h via a syringe pump,keeping the reaction at 55° C. When a total of 8 mL 1N HCl was added(pH=10.1), a ˜0.5 mL aliquot solution was removed to a 4 mL size vialand ˜2 mg solabegron-zwitterion seed was added. All of the seeddissolved. The above procedure to find a proper seeding point, wasrepeated at pH=9.4, 8.8, 8.2, 7.8 and 7.6. Seeds were not survived underall of these conditions.

When the reaction mixture reached a pH of 7.5 (total 13 mL 1N HCladded), 50 mg of solabegron-zwitterion seed (Form I) was added and thebatch turned hazy. The slurry was checked by PLM which showed a new typeof crystal (by morphology). After a total 20 mL of 1N HCl was added thereaction mixture was at a pH of 6.9. the addition of HCl was stopped.The reaction mixture was aged at 55° C. for 3.5 h, cooled to 20° C. over5 h, then aged at 20° C. for 16 h. An additional 0.2 mL of 1N HCl wasadded over 5 min at 20° C. to adjust the reaction mixture pH from 8.0 to7.1. The reaction mixture was aged at 20° C. for 1 h. The sample forPLM, remained as a new crystal morphology. The solids were isolated byfiltration and the filter cake was washed with 20:80 v/v IPA/water 1×20mL, followed by water 2×20 mL. The solid was dried at ambienttemperature under vacuum for 3 h, followed by drying in a vacuum oven at50° C. for 20 h. 5.0 g off-white dry solid was obtained and a sample ofthe solid was analyzed by XRPD for crystal form (giving a distinct newXRPD pattern, FIGS. 7, and 14), and PLM for crystal morphology(distinctively different from zwitterion Form I, FIG. 6). The solidcontains 2.8 wt % of water by KF, 2.1 wt % of IPA by GC.

Procedure B: HCl in IPA Procedure

Solabegron-Na stock solution (50.0 g, 10 wt % in 1:1 v/v IPA/water,equiv to 5.0 g of solabegron zwitterion, 12.17 mmol) was charged into anEasyMax 100 mL vessel with temperature probe, pH probe (pre-calibratedat pH 4.00, 7.00, and 10.00), condenser and nitrogen bubbler. Theagitation rate was set to 450 rpm, the reaction mixture was heated to55° C. over 30 min. The reaction pH was 13.2. 1-1.2N HCl in IPA wasadded at a rate of 7.5 mL/h via a syringe pump at 55° C. HCl additionwas stopped when pH 7.1 was reached (total 13 mL HCl added), no oiledout was observed. A crystalline zwitterion seed (the dry solids fromProcedure A, solabegron zwitterion Form II, 2%, 100 mg) was added in oneportion, and seed beds formed instantly. The slurry was aged at 55° C.for 3 h. The reaction mixture was cooled to 20° C. over 5 h. Then agedat 20° C. for 5-20 h. The pH of the reaction mixture was adjusted to pH7.2 from 8.0 by adding 1-1.2N HCl in IPA (5 mL) over 20 min. The slurrywas aged at 20° C. for 2-5 h. The solids were isolated by filtration andthe filter cake was washed with 20:80 v/v IPA/water 1×20 mL, followed bywater 2×20 mL. The solids were dried at ambient temperature under vacuumfor 3 h, followed by drying in a vacuum oven at 50° C. for 20 h. 4.42 goff-white dry solids was obtained. The solid sample was analyzed by XRPDfor crystal form, and PLM for crystal morphology (FIG. 6).

Crystal form of solabegron zwitterion (designated as Form II) wasgenerated from Procedure A, seeded with solabegron zwitterion Form I.Procedure B was seeded with solabegron zwitterion Form II (thezwitterion product from Procedure A) and produced solabegron zwitterionForm II.

The XRPD pattern of the solabegron zwitterion from Procedure A (see FIG.7), designated as solabegron zwitterion Form II, is distinctly differentfrom the solabegron zwitterion Form I crystal (Form I). FIG. 8 shows theTGA plot of Form II vs. Form I, revealing two steps of wt. losses forForm II, one from 25 to 100° C. by 2.6 wt % and another from 100 to 150°C. by another 3.7 wt %. DSC analysis of solabegron zwitterion Form II,as shown in FIG. 9, reveals three thermal events, peaked around 67° C.(very broad), 131° C. (broad) and 180° C. (narrow), respectively.Correlating with the TGA data, the two events at lower temperatures arelikely related to solvent losses.

¹H-NMR and KF analyses of solabegron zwitterion from Procedure A samplegave 2.8 wt % H₂O and 4.3 wt % IPA, respectively. The data approximatethe wt % losses by TGA analysis (i.e., 2.6 wt % and 3.7 wt %,respectively).

The relative stability of solabegron zwitterion Forms I and II wasevaluated via slurry conditioning of either solabegron zwitterion Form Ior a mixture of solabegron zwitterion Forms I and II in IPA/H₂O withdifferent ratio, for a) confirmation of relative stability of the twosolabegron zwitterion forms, and b) rational process design and control.The table in FIG. 10 lists the testing conditions and results.Solabegron zwitterion Form II resulted from all tested conditionsstarting with either solabegron zwitterion Form I alone or a mixture ofsolabegron zwitterion Forms I and II, indicating solabegron zwitterionForm II is more stable than solabegron zwitterion Form I. This supportsthat solabegron zwitterion Form II should be the targeted polymorph ofisolation for robust purity control of the product.

Procedure C: Solabegron-Zwitterion Crystallization

Solabegron-Na stock solution (50.46 g, 12.8 wt % in 1:1 v/v IPA/water)was charged into a 100 mL vessel; 12 mL 1:1 v/v IPA/water was added andthe reaction mixture was heated to 55° C. over 20 min. 2N HCl (12 mL, in1:1 v/v IPA/water) was added via a dosing unit over 120 min at 55° C.HCl addition was paused when the pH reached 7.0 (total 14.9 mL HCladded). Solabegron zwitterion (form II) seed (3%, 194 mg, 596-172) wasadded in one portion, and seed bed gradually formed. The thin slurry wasaged at 55° C. for 30 min, and the pH went up to 7.3 to 7.5 during thisperiod. HCl was added continuously until a pH of 6.8 was reached (total2.3 mL 2N HCl added over 23 min). HCl addition was stopped and theslurry was aged at 55° C. for 30 min. The mixture was cooled to 20° C.over 5 h. then aged at 20° C. for 2 h. 2N HCl (1.0 mL) was added over 10min at 20° C. and the slurry was aged at 20° C. for 5-15 h. The pH wasadjusted to 6.8-7.2 (if pH>7.2) by adding slightly more 2N HCl (amountdepending on the pH) over 5-30 min. The slurry was aged at 20° C. for1-5 h. Solid solabegron zwitterion was isolated by filtration. The cakewas washed with 20:80 v/v IPA/water 1×25 mL, followed by water 2×25 mL.The solid was then dried under vacuum at 25° C. for 3 h. The solid gave99.43 LCAP by HPLC.

Example 3: Preparation of the Solabegron HCl Salt (Formula I-HCl)

Procedure A

Solabegron zwitterion solid (4.81 g, 87.6 wt %, equivalent to 4.21 gpure) was mixed with degassed IPA (21 mL) and degassed HPLC water (19.4mL), in an EasyMax 100 mL vessel. The mixture was heated to 65° C., and6N HCl (1 equiv) was added in one portion to dissolve all the solid. Theratio of IPA to water was 1:1 v/v. The solution was then cooled to 55°C., 2% seeding (84 mg) was applied by adding the seed in one portion.After aging at 55° C. for 30 min, the resulting mixture was cooled to 0°C. over 5 h, and held at 0° C. for 15 h. The slurry sample was anagglomerate of fine particles by PLM. The solid was isolated byfiltration, the wet cake was washed with 20:80 v/v IPA/water 1×20 mL,and water 2×20 mL. The wet cake, as beige solid, gave 99.1 A % by LC(MR325, 242 nm) of solabegron HCl salt.

Procedure B

Well purified solabegron zwitterion Form II with 99.4 A % purity LC wasconverted into solabegron HCl salt. The experiment was carried out at 5g-solabegron zwitterion scale in a 100 mL EasyMax vessel. The solabegronzwitterion solids were dissolved readily at 68° C. after 6N HCl (˜1.05equiv) was charged. Seed (2%, 100 mg, HCl salt Form I) was added in oneportion and a slurry was generated instantly. The batch slurry wascooled to 0° C. over 5 h. After the batch was aged at 0° C. for 8-12 h(overnight), the product was isolated by filtration. The dried productgave 99.8 A % by LC (MR325). The solid was confirmed as Form I by XRPD(FIG. 11), with crystal morphology similar to previous HCl salt by PLM(see FIG. 12). The results from different purity of solabegronzwitterion indicated that as long as zwitterion purity is high enoughthe existing process for HCl salt crystallization works quite well (withno obvious issue).

Procedure C

An EasyMax 100 mL crystallizer with baffle, was charged with solabegronzwitterion (Form II, 4.71 g=4.0 g pure, 9.73 mmol, 99.0 LCAP), IPA (20mL), and water (18.4 mL, Chromasolv for HPLC) at ambient temperature.The agitation rate was set to 300 rpm. The reaction mixture, as slurry,was heated to 68-70° C. over 30 min. HCl (6 N, 1.95 mL, 1.2 equiv) wasadded at 68-70° C. in one portion. The reaction mixture turned a clearsolution, pH was 0.3-0.4 at 69° C. The reaction mixture was cooled to62° C. over 20-30 min. and remained as most clear solution. The batchturned to a slurry and the agitation was set to 500 rpm. Solabegron HClsalt seed (20 mg) was added in one portion. After the batch was aged at62° C. for 15-20 min, the resulting slurry was cooled to 0° C. over 5 hlinearly; and PLM was checked during cooling. The reaction mixture wasaged at 0° C. overnight. A slurry sample was taken for PLM, the reactionmixture was at a pH of 2.3. The product was isolated by filtration, thewet cake was washed by 9:1 v/v water/IPA (1×15 mL), followed by water(2×15 mL). After drying at RT with vacuum suction for 3 h, the partiallydried solid was further dried in vacuum oven (50° C.) with nitrogensweep for 20 h. Solabegron-HCl (Formula II) was obtained as off-whitesolid (4.32 g) in 93.8% isolated yield after subtracting seed.

Example 4: Initial Preparation of the Solabegron Zwitterion Form I

To a 250 mL reactor was added imidazoline IV (46.96 g) in toluene (180mL). The resulting solution was heated to 55° C. and(R)-2-(3-clorophenyl)oxirane (22.69 g) was added with stirring. Thereaction mixture was heated to 120° C. for 26 h. The reaction mixturewas cooled to 83° C. and transferred to a 1 L reactor. Isopropyl alcohol(203 mL) and water (203 mL) were added to the reactor. Aqueous sodiumhydroxide (42.5 mL, 32% wt./wt.) was added at a temperature above 60° C.The reaction mixture was distilled to remove toluene. IPA (140 mL) wasadded to the reactor and the reaction mixture was filtered through acarbon disk. Concentrated HCl (18.8 mL) was added to crystallize thezwitterion, which was washed with water (2×90 mL) and IPA (1×90 mL) withvacuum filtration to yield 36.32 g (76%) of small crystals that wereconfirmed by spectroscopy and XRPD to be the desired solabegronzwitterion. See FIG. 13.

Although the present disclosure has been described in considerabledetail with reference to certain preferred versions thereof, otherversions are possible. Therefore, the spirit and scope of theapplication should not be limited to the description of the preferredversions described herein.

All features disclosed in the specification, including the abstract anddrawings, and all the steps in any method or process disclosed, may becombined in any combination, except combinations where at least some ofsuch features and/or steps are mutually exclusive. Each featuredisclosed in the specification, including abstract and drawings, can bereplaced by alternative features serving the same, equivalent or similarpurpose, unless expressly stated otherwise. Thus, unless expresslystated otherwise, each feature disclosed is one example only of ageneric series of equivalent or similar features. Various modificationsof the application, in addition to those described herein, will beapparent to those skilled in the art from the foregoing description.Such modifications are also intended to fall within the scope of theappended claims.

Throughout the above specification a number of references have beencited and or referred to it is to be understood that unless specificallynoted, all references cited in the above specification and or referredto in the above specification are hereby incorporated by reference intheir entirety.

What is claimed is:
 1. An isolated compound according to Formula II:

or a pharmaceutically acceptable salt or stereoisomer thereof, in theform of a hydrated isopropanol solvate.
 2. The isolated compoundaccording to claim 1, wherein the isolated compound is a crystallinesolid.
 3. The isolated compound according to claim 1, wherein thecompound is at least about 97.0% by weight pure.
 4. The isolatedcompound according to claim 1, wherein the compound is at least about99.0% by weight pure.
 5. The isolated compound according to claim 1,wherein the compound is at least about 99.5% by weight pure.
 6. Theisolated compound according to claim 1, wherein the compound is at leastabout 99.9% by weight pure.
 7. The isolated compound according to claim1, wherein no single impurity is present in an amount greater than about0.5% by weight.
 8. The isolated compound according to claim 1, whereinno single impurity is present in an amount greater than about 0.25% byweight.
 9. The isolated compound according to claim 1, wherein no singleimpurity is present in an amount greater than about 0.10% by weight. 10.The compound of claim 1 wherein the hydrated isopropanol solvate is 3equivalents of the compound of Formula II:1 equivalent of isopropanol:2equivalents water.
 11. A pharmaceutical composition comprising: atherapeutically effective amount of a solid compound according toFormula II:

or a pharmaceutically acceptable salt or stereoisomer, in the form of ahydrate of isopropanol solvate; and at least one pharmaceuticallyacceptable carrier or excipient.
 12. The composition according to claim11, further comprising one or more additional therapeutic agentsselected from the group consisting of: antimuscarinic agents; alphaadrenoceptor blockers; 5-alpha reductases; and phosphodiesterases-5inhibitors.
 13. The pharmaceutical composition of claim 11 wherein thehydrated isopropanol solvate is 3 equivalents of the compound of FormulaII:1 equivalent of isopropanol:2 equivalents water.